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Background Patients with hypertrophic cardiomyopathy (HCM) are not currently considered at elevated risk for infective endocarditis (IE) and are excluded from guideline-directed antibiotic prophylaxis, despite structural and haemodynamic features that may predispose to infection.Methods This retrospective cohort study used real-world data from the TriNetX research network, a multicentre electronic health record platform. Adults aged ≥45 years with an ambulatory encounter between 1 January 2015 and 31 December 2019 and a diagnosis of HCM were identified and propensity score matched 1:1 to controls without HCM. A reference group of patients with prior valve intervention was also analysed. The primary outcome was 5-year cumulative incidence of IE, determined by International Classification of Diseases-10 codes. HRs and 95% CIs were calculated using Cox proportional hazards models.Results Among 18 177 matched HCM-control pairs (mean (SD) age, 65.7 (10.4) years; 43.8% female), the 5-year cumulative incidence of IE was 3.25% in the HCM group and 1.31% in controls (HR, 2.62; 95% CI 2.20 to 3.12; p<0.001). In the valve intervention cohort (n=1916), IE incidence was 6.46% versus 1.52% in controls (HR, 4.21; 95% CI 2.62 to 6.75; p<0.001). In an exploratory subgroup of 231 HCM patients treated with mavacamten, no IE cases occurred during the 1-year follow-up period.Conclusions Patients with HCM had more than twice the 5-year risk of IE compared with matched controls and approximately half the risk seen in patients with valve interventions. HCM may represent an intermediate-risk group not currently addressed in prophylaxis guidelines.